Circulating microRNAs in metastatic colorectal cancer (mCRC) patients (pts) treated with regorafenib

Introduction: Regorafenib is indicated for the treatment of mCRC patients who have failed all other therapies. Nevertheless a substantial percentage of patients experiences rapid disease progression (PD) and serious adverse events may occur. For these reasons, clinical and/or molecular markers able to improve the cost/benefit ratio are urgently needed. Circulating microRNAs (c-miRNAs) have been recognized as possible prognostic and diagnostic markers in mCRC. The aim of this study was to describe the early changes in plasma levels of 10 selected c-miRNAs during the treatment with regorafenib and to investigate their correlation with clinical outcome.Methods: Plasma samples of patients treated with regorafenib at our Institution were collected at baseline (D1) and after 15 days of treatment (D15). Plasma levels of c-miR-17, c-miR-21, c-miR-29, c-miR-34, c-miR-92, c-miR-126, c-miR-141, c-miR-221, c-miR-601, c-miR-760 were analysed by means of real-time PCR. Paired levels at D1 and D15 were compared by means of Wilcoxon test for each c-miRNA. C-miRNAs showing significant changes were further analysed in order to identify possible correlations with outcome.Results: Thirty-four patients were included in the present study. Main characteristics were the following: M/F = 50%/50%; median age = 65 (range 48-78 years); ECOG-PS 0/1-2 = 71%/29%; time from diagnosis of metastases </ ? 18 months 15%/85%. Median PFS and OS were 2.4 and 6.5 months, respectively. One (3%) patient achieved a response and 16 (47%) had disease stabilization (disease control rate: 50%). As compared to D1, the following c-miRNAs increased at D15: c-miR-601 (p = 0.01), c-miR-141 (p = 0.04) and c-miR-21 (p = 0.06). Despite a median increase in the overall population, 12 (35%) out of 34 patients showed reduced level of c-miR-21 at D15. Nine out of 12 (75%) patients with reduced levels of c-miR-21 achieved disease control, as compared to 8 out of 23 (35%) patients with increased levels (Fisher \u27s Exact Test, p = 0.035). Median PFS of patients with increased and decreased level of levels of c-miR-21 were 2.1 and 3.9 months, respectively (HR = 1.89 95%CI 0.92-4.14 p = 0.08). Data on OS are not yet mature. Early modifications of c-miR-21 levels showed a sensitivity of 82% in predicting benefit from regorafenib.Conclusion: The early modulation of c-miR-21 levels may predict benefit from regorafenib in terms of disease control. These results need validation in independent series

A hypothesis of a redistribution of North Atlantic swordfish based on changing ocean conditions

Conflicting trends in indices of abundance for North Atlantic swordfish starting in the mid-to late 1990s, in the form of fleet specific catch-per-unit-effort (CPUE), suggest the possibility of a spatial shift in abundance to follow areas of preferred temperature. The observed changes in the direction of the CPUEs correspond with changes in trends in the summer Atlantic Multidecadal Oscillation (AMO), a long term mode of variability of North Atlantic sea surface temperature. To test the hypothesis of a relation between the CPUE and the AMO, the CPUEs were made spatially explicit by re-estimating using an “areas-as-fleets” approach. These new CPUEs were then used to create alternative stock histories. The residuals of the fit were then regressed against the summer AMO. Significant, and opposite, relations were found in the regressions between eastern and western Atlantic areas. When the AMO was in a warm phase, the CPUEs in the western (eastern) areas were higher (lower) than predicted by the assessment model fit. Given the observed temperature tolerance limits of swordfish, it is possible that either their preferred habitat, prey species, or both have shifted spatial distributions resulting in conflicting CPUE indices. Because the available CPUE time series only overlaps with one change in the sign of the AMO (~1995), it is not clear whether this is a directional or cyclical trend. Given the relatively localized nature of many of the fishing fleets, and the difficulty of separating fleet effects from changes in oceanography we feel that it is critical to create CPUE indices by combining data across similar fleets that fish in similar areas. This approach allowed us to evaluate area-specific catch rates which provided the power to detect basin-wide responses to changing oceanography, a critical step for providing robust management advice in a changing climate.Postprin

Single nucleotide polymorphisms in miRNA binding sites of nucleotide excision repair-related genes predict clinical benefit of oxaliplatin in folfoxiri plus bevacizumab: Analysis of the tribe trial

Background: The nucleotide excision repair (NER) pathway participates in platinuminduced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEVtreated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV

the role of adjuvant therapy in resectable sba a different clinicians attitude with a relevant impact on outcome

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The Role of p53 Expression in Patients with RAS/BRAF Wild-Type Metastatic Colorectal Cancer Receiving Irinotecan and Cetuximab as Later Line Treatment

Background: Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. Objective: In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. Patients and Methods: p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan–Meier method, while the log-rank test was used for survival comparison. Results: Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. Conclusions: In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients

A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09–2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34–0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29–0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC

lba22negative hyper selection of ras wild type wt metastatic colorectal cancer mcrc patients randomized to first line folfox plus panitumumab pan followed by maintenance therapy with either 5fu lv plus pan or single agent pan translational analyses of the valentino study

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development of a new clinical nomogram including velocity rate of disease progression to predict outcome in metastatic colorectal cancer patients treated with bevacizumab beyond progression a subanalysis from tribe trial

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p 207clinico pathological and molecular characterization of braf mutant metastatic colorectal cancer mcrc are all mutations created equal

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po 472 microrna as biomarkers of resistance to regorafenib in metastatic colorectal cancer patient

Introduction Regorafenib demonstrated efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. Limited clinical benefit in unselected patient populations highlights the unmet need for better patient selection and identification of mechanisms of action. MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis, carcinogenesis and control multiple oncogenic pathways. Numerous miRs deregulation in mCRC are associated with clinical outcome and cancer progression. Material and methods We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients with biopsiable metastases. Tissue biopsies were obtained at baseline (BL), after 2 months of treatment, and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in BL serum of all patients by NanoString nCounter platform and validated with digital droplet (dd)PCR in serum, plasma and exosomes and by In Situ Hybridization (ISH) in matching tissue biopsies. Fisher's exact test investigated potential associations between patient groups and categorical variables whilst t-test or non-parametric equivalent tests were used for continuous variables. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. The Kaplan-Meier method summarised the survival estimates while the Cox proportional hazards model used to compare the survival rates between patient groups with and without adjustment for the effect of covariates. Results and discussions MiR expression was tested in 43 BL sera. Dysregulation in 28 miRs was associated with PFS and/or OS. Among these miRs, up-regulation of miR-652–3 p and down-regulation of miR-3614–3 p was associated with worse PFS and OS. Results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed dysregulation of two miRs in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance. Validation in an independent patient's cohort (n=70) is ongoing. Functional experiments to define miR-mediated resistance are ongoing. Conclusion Circulating miR-652–3 p and miR-3614–3 p might be exploited as biomarkers for the upfront selection of patients' candidate to regorafenib treatment and might be used to track and forecast acquired resistance to treatment